They myelin-associated glycoprotein (MAG) is selectively localized in the periaxonal part of PNS and CNS myelin sheaths where it is likely to be involved in glia-axon interactions. This function was supported by recent immunocytochemical studies in experimental pathological situations (iminodipropionitrile neuropathy and aging quaking mice) showing a correlation between the maintenance of the Schwann cell-axon junction and the presence of MAG. During development, the accumulation of MAG slightly precedes that of PO glycoprotein in the PNS and myelin basic protein in the CNS, suggesting a function early in the process of myelinogenesis. Metabolic studies in 14-day-old and adult rats have shown that MAG is relatively stable for 1 to 2 weeks after synthesis and then turns over with a half-life of about 3 weeks. In Trembler mice, affected by severe hypomyelination of the PNS, the amount of MAG in the sciatic nerve is nearly normal but it has a higher apparent molecular weight than control MAG. A panel of monoclonal antibodies reacting with polypeptide and carbohydrate sites on the MAG molecule has now been produced by hybridoma techniques in mice. MAG is the myelin antigen that reacts with monoclonal IgM produced in patients with paraproteinmia associated with peripheral neuroparthy. The IgM produced by these patients reacts with human MAG but not rat MAG, and preliminary experiments indicate that the antigenic site is in the carbohydrate portion of the MAG molecule. Several of the experimental mouse IgM monoclonals exhibit the same specificity as that produced by the patients. Recent studies with monoclonal antibodies have also demonstrated a shared antigenic determinant between human MAG and circulating natural killer cells. No evidence of humoral to MAG has been detected in multiple sclerosis patients, but about 20% of these patients show sensitization of peripheral blood lymphocytes to MAG and myelin basic protein in thymidine incorporation studies.